Data_Sheet_1_Modulation of the Aβ-Peptide-Aggregation Pathway by Active Compounds From Platycladus orientalis Seed Extract in Alzheimer’s Disease Models.DOCX

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neuronal loss, cognitive impairment, and aphasia. Aggregation of β-amyloid (Aβ) peptide in the brain is considered a key mechanism in the development of AD. In the past 20 years, many compounds have been developed to inhibit Aβ aggregation and accelerate its degradation. Platycladus orientalis seed is a traditional Chinese medicine used to enhance intelligence and slow aging. We previously found that Platycladus orientalis seed extract (EPOS) inhibited Aβ-peptide aggregation in the hippocampus and reduced cognitive deficits in 5×FAD mice. However, the mechanisms of these effects have not been characterized. To characterize the protective mechanisms of EPOS, we used a transgenic Caenorhabditis elegans CL4176 model to perform Bioactivity-guided identification of active compounds. Four active compounds, comprising communic acid, isocupressic acid, imbricatolic acid, and pinusolide, were identified using 13C-and 1H-NMR spectroscopy. Furthermore, we showed that isocupressic acid inhibited Aβ generation by modulating BACE1 activity via the GSK3β/NF-κB pathway in HEK293-APPsw cells. These findings showed that EPOS reduced cognitive deficits in an AD model via modulation of the Aβ peptide aggregation pathway.

阿尔茨海默病（Alzheimer’s disease，简称AD）是一种以神经元丢失、认知障碍和失语为特征的神经退行性疾病。大脑中β-淀粉样蛋白（β-amyloid，简称Aβ）肽的聚集被认为是AD发病的关键机制。在过去二十年里，许多化合物被开发出来以抑制Aβ聚集并加速其降解。侧柏种子是传统中医中用于增强智力和延缓衰老的药材。我们先前发现，侧柏种子提取物（Platycladus orientalis seed extract，简称EPOS）可以抑制海马体中的Aβ肽聚集并减少5×FAD小鼠的认知缺陷。然而，这些效果的机制尚未得到阐明。为了阐明EPOS的保护机制，我们采用了一种转基因秀丽隐杆线虫Caenorhabditis elegans CL4176模型，通过生物活性指导识别活性化合物。利用13C和1H核磁共振波谱法鉴定了四种活性化合物，包括原儿茶酸、异海松酸、叠瓦酸和松脂素。此外，我们证实异海松酸通过调节GSK3β/NF-κB通路来抑制BACE1活性，从而在HEK293-APPsw细胞中抑制Aβ的产生。这些发现表明，EPOS通过调节Aβ肽聚集途径，在AD模型中减少了认知缺陷。